Optimizing Personalized Therapy for Rheumatoid Arthritis Using a Novel Drug Combination of Representative Bioactive Compounds of a Classic Chinese Herbal Formula

Background: Personalized therapy of rheumatoid arthritis (RA) based on traditional Chinese medicine cold and hot syndromes is extremely essential for optimizing therapeutic efficacy. Wutou Decoction (WTD) achieves favorable therapeutic response in treating RA-cold syndrome. However, its material basis and potential mechanisms remain unclear. Herein, we aimed to identify the representative bioactive compounds (BACs) of WTD against RA-cold syndrome. Methods: Microarray analysis was performed to screen RA-cold and RA-hot-syndrome-related genes, and WTD effect genes. Representative BACs and candidate targets of WTD were identified by integrating network analysis, chemical profiling, absorption-distribution-metabolism-excretion evaluation and molecular docking simulation. Both in vivo and in vitro experiments were performed to evaluate therapeutic effects of the BAC-combination against RA-cold syndrome. Findings: ALOX15B-PPAR-γ-PTGS2-FGF2-IL-1β-c-JUN-MMP13-TGF-β1 signal axis, mainly involved into regulating thermogenesis and energy metabolism, as well as maintaining the balance of inflammation-immune system, was demonstrated to be a candidate network target of WTD against RA-cold syndrome. The four-BAC-combination, including Beiwutine/10-OHmesaconitine, Talatizidine, Paeoniflorin and Glabrene, regulating the signal axis, were formed to be a potential drug for treating RA-cold syndrome. Further experiments demonstrated that this combination efficiently reversed the pathological changes of RA-cold syndrome by regulating the ALOX15B-PPAR-γ-PTGS2-FGF2-IL-1β-c-JUN-MMP13-TGF-β1 signal axis. Interpretation: This study identified the novel four-BAC-combination, which may represent the therapeutic efficacy and syndrome differentiation-based treatment characteristics of WTD against RA. The findings shed light into the modernization of TCM formulae and promoted new drug discovery. Funding Statement: National Natural Science Foundation of China (81630107 & 81673834), and Fundamental Research Funds for the Central public welfare research institutes (L2017018). Declaration of Interests: The authors declare that there is no conflict of interests regarding the publication of this paper. Ethics Approval Statement: All procedures in the current study were performed in accordance with the ethical standards of the Center for Laboratory Animal Care, China Academy of Chinese Medical Sciences.